Interferons (IFNs) are proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, bacteria, parasites, tumor cells, and donor tissue. Interferons belong to the large class of glycoproteins known as cytokines. Three types of IFNs (Type I, II, and III) have been described which signal through unique receptor heterodimers. Because IFNs are robustly produced in response to viruses and have widespread effects on most cells of the immune system, IFNs are considered important molecules in linking early or innate immune responses to infection with later adaptive immune responses.
Since the discovery of IFN in 1957 as a substance able to induce resistance to viral infection, IFNs are now known as pleiotropic cytokines with diverse activities, ranging from the induction of viral resistance in cells, to the regulation of both innate and adaptive arms of the immune response. Antiviral activities of IFNs are often accompanied by anti-proliferative and pro-apoptotic effects in various cells. IFNs also upregulate MHC(HLA) class I antigen expression and induce expression of immunoproteasome subunits. These IFN activities modulate antigen presentation in virus-infected cells, making these cells a better target for CD8+ cytotoxic T cells (CTLs).
IFNs are also major activators of natural killer (NK) cells and CTLs, both of which act on virus-infected cells, or cells with other intracellular pathogens. IFNs promote the differentiation of monocytes into monocytic or common dendritic cells, the major antigen-presenting cell. IFNs have direct effects on B-cell maturation and class-switching, and are also recognized for their antitumor activities. Presently, IFNs are used clinically as a treatment for several malignancies, including cancer.
However, the potency and pleiotropic effects of IFNs requires that they be maintained under tight transcriptional regulation, with the normal state of most genes being “off”. Transcription up-regulation for most classical type I IFNs is subject to sophisticated systems that monitor the presence of viruses or other pathogen-related stimuli and provide robust and well-tuned production of type I IFNs. Expression of type III IFNs appears to be regulated through the similar pathways. Recent data suggest involvement of IFNs in the pathogenesis of some immune diseases, for example, autoimmune diseases, systemic lupus erythematosus (SLE), and Sjögren's syndrome; acute allograft rejections; septic shock; and exaggerated antiviral response induced by certain viruses or viral strains.
Viruses have developed many strategies to circumvent IFN-induced antiviral protection, generally interfering with IFN signaling. Poxviruses form a large family of double-strand DNA viruses. Some poxviruses are extremely virulent, and include variola virus (VARV) which causes smallpox with high mortality rate, as well as the genetically related vaccinia virus (VACV). VACV encodes two secreted proteins which function as IFN antagonists: B8R protein is the soluble receptor of IFN-γ, whereas B18R protein binds IFN-α, IFN-β and IFN-ω and suppresses interaction of IFNs with their membrane-bound receptor complexes. Most poxviruses encode proteins homologous to vacvB18R which are predicted to possess similar abilities to neutralize IFN-α/β.
The Yaba-like disease virus (YLDV), which causes vesicular skin lesions in primates and can be transmitted to humans, encodes the 136R protein which bears slight homology (about 27%) to vacvB18R protein. However, the ability of yldv136R to inhibit biological activities of IFNs, or the ability of vacvB18R to neutralize type III IFNs and novel members of the type I IFN family, IFN-κ and IFN-γ is currently unknown.
Due to the involvement of interferons in many immunological conditions, the IFN signaling pathway remains highly relevant as a target for further research as well as therapeutic intervention. Not surprisingly, the discovery of an INF antagonist agent that exhibits specificity for IFN proteins, especially those of multiple types, would be valuable as a therapeutic for treating disorders caused by hyper-stimulation of the IFN signaling system. For example, there are currently no known antagonists of type III interferons. On the other hand, agents that are antagonists of viral INF receptors are potentially useful for the treatment and prevention of viral infection and proliferation.